FI107256B - Process for the preparation of 6- (2-hydroxyethylamino) or 6 - [(2-hydroxyethyl) aminoalkyl] -5,11-dioxo-5,6-dihydro-11-H-indeno (1,2-c) isoquinolines - Google Patents

Abstract

New 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2 -c]isochinoline derivatives represented by general formula (I), in which X stands for the number of carbon atoms from 0 to 5 in aminoalkyl group situated on nitrogen atom in position 6 of the indenoisochinoline fundamental structure, their salts with inorganic and organic acids and their derivatives were described. Antitumorously effective indenoisochinoline derivatives are most preferably prepared by the process in which the indeno[1,2-c]isocoumarine and/or 1-methoxy-2-(2-methoxycarbonylphenyl)-1-inden-3-one, respectively, comprises reacting with N-(hydroxyethyl)alkylen diamine in a medium of suitable aprotic solvent, preferably dimethylformamide, and at increased temperature. Another process for the preparation comprises reacting 6-(X-chloroalkyl)-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isochinolines with 2-aminoethanol in suitable solvent, preferably dimethylformamide, in the presence of anhydrous potassium carbonate. New compounds, their derivatives and salts are useful for the preparation of drugs and compositions for the treatment of malignant neoplasias in mammals.

Description

107256

Method for the preparation of anti-tumor 6- (2-hydroxyethylamino) or 6 - [(2-hydroxyethyl) aminoalkyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinolines - Förfarande 6-5 (2-hydroxyethylamino) eller 6 - [(2-hydroxyethyl) aminoalkyl] -5,11-dioxo-5,6-dihydro-11-H-indeno [1,2-c]. This invention relates to a process for preparing 6- (2-hydroxyethylamino) 10 or 6 - [(2-hydroxyethyl) aminoalkyl] -5,11-dioxo-5,6-

for the preparation of dihydro-11 H -indeno [1,2-c] isoquinolines of general formula I

J ^ (CH2) X

0 (I) wherein X represents the number of carbon atoms between 0 and 5 in the aminoalkyl group bonded to the nitrogen atom at position 6 of the indenoisoquinoline basic structure, or their salts with inorganic and organic acids.

The compounds of the formula I (eg, the bases of the compounds of the general formula I) and their salts with pharmaceutically and pharmacologically acceptable acids have useful antitumor activity and may be used alone or in combination with other antineoplastic agents for the treatment of suitable biological targets, in particular in mammals.

1072ϊ) 6 2

Certain indeno [1,2-c] isoquinoline derivatives have been discussed in the relevant literature as alkaloid cryotropin degradation products [Perkin W. H: J. Chem. Soc.

109, 815 (1916); 115, 713 (1919); 9y-5 ke S. F., Brown D. W.; Tetrahedron 24, 1455 (1968)]. 1 H -indeno [1,2-c] isoquinoline and / or 5-hydroxy-11 H -indeno [1,2-c] isoquinoline N-oxide was prepared by reaction of 1 H -indeno [1,2-c ] isocoumarin with ethanolic ammonia and / or hydroxylamine [Chatterjea JN, Muk-10 dye H .: J. Indian Chem. Soc. 37, 379 (I960)].

5,11-Dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoku-15 marine prepared by high pressure reaction of 11-oxo-11 H -indeno [1,2-c] isocoumarin and ethanolic ammonia has been described [Wawzonek S., Stowell JK, Karll K.

E .: J. Org. Chem. 31, 1004 (1966)].

Indenoisoquinoline analogs of the highly toxic nitidine and phagaronin have also been prepared [Cushman M., 20 Mohan P., Smith E. C. R .: J. Med. Chem. 27, 544 (1984);

Cushman M., Mohan P .: J. Med. Chem. 28, 1031 (1985)].

Said indenoisoquinoline compounds did not show any useful biological activity except for the indenoisoquinoline analogs of fagarin and nitidine which showed weak antitumor activity.

To our knowledge, the compounds of this invention, ¢ -30 (2-hydroxyethylamino) or 6 - [(2-hydroxyethyl) aminoalkyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c ] isokinc lines of the general formula I wherein X represents the number of carbon atoms between 0 and 5 in the aminoalkyl group bonded to the nitrogen atom at mass 6 of the indenoisoquinoline basic structure (e.g. bases of compounds of general formula I) and their salts with pharmaceutically and pharmacologically acceptable acids form novel, previously uncharted class 107256 3 compounds which, unexpectedly, exhibit remarkable anti-tumor activity "in vitro" and "in vivo" not yet described. The main advantage of the new compounds is their good efficacy even when administered orally, with low toxicity and synthetic accessibility compared to the substances (antibiotics).

As a result of extensive research, new 6- (2-hydroxyethylamino) or 6 - [(2-hydroxy-10-ethyl) aminoalkyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2 -c] isoquinolines of general formula I, wherein X represents the number of carbon atoms between 0 and 5 in the aminoalkyl group bonded to the nitrogen atom at position 6 of the indenoisoquinoline basic structure, and their salts with inorganic and organic acids, and antitumor activity may be used alone or in combination with other anti-tumor drugs for the treatment of suitable biological targets, particularly mammals.

20

The indeno [1,2-c] isoquinolines of general formula I can be prepared in three ways, all of which are conventional in nature.

The starting materials used were: 1. Easily available 11-oxo-11 H -indeno [1,2-c] isocoumarin (II) (cf. Pailer M., Worther H., Meller A.: Mh.

Chem. 92, 1037 (1961)], 2. 1-methoxy-2- (2-methoxycarbonylphenyl) -1-inden-3-one (III) [Pailer M., et al .: 1c] and 3. 6- ( chloroalkyl) -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinolines (IV).

The indeno [1,2-c] isoquinolines of general formula I (X = 0-5) are preferably prepared by condensation of indeno [1,2-c] isoquumarin (II) and / or 1-methoxy-2- (2) -methoxycarbonylphenyl) -1-inden-3-one (III) and N- (hydroxyethyl) diamine or N- (hydroxyethyl) alkylenediamine-107256 4-alkyl having 1-5 carbon atoms in hot dimethylformamide. Another process for preparing Type I-like compounds is the condensation reaction between Type IV 6- (chloroalkyl) -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinolines and ethanolamine in dimethylformamide in the presence of anhydrous potassium carbonate.

θίτ ° \ I n N. ----- \ —n

NH 2 (CH 2> xNIP ^ V ^ -OH

och3 m viwN- (ch2) x-nh ^^ 0 »cooch3 o

jf I

o. II2N - ^^ OH

] -Ί | η k2co3, DMF

(CH2) x-ci 0 IV

10

The antitumor activity of the compounds of the formula I has been investigated by testing compounds of the chemical group "in vivo" against experimental basal cell tumors such as Ehrlich solid form (STE, initial 15 mammary gland cancer), tumor HK (also transmissible primary mammary gland cancer, Kr2), S37 watery abdominal sarcoma, Nemeth-Keller lymphoma (NK), all detected in mice H, Gardner's lymphosarcone (LsG, found in mice C3H), P388 and / or L1210 leukemic, 20 (in DBA2 mice), metastatic B16 5 (dark cancer) C57B1 / 6 in mice), and Yoshida's Water Hemorrhoidal Endothelial Cancer (Y, found in Wistar rats), in experiments reported by V. Jelinek [Neoplasma 12, 469 (1965); Neo-Plasma 7, 146 (1960)] and in "in vitro" experiments using 5 radioactive nucleic acid and protein precursors M. Mikon et al. according to Cancer Res 39, 4242 (1979); Neoplasma 26: 449 (1979); Neoplasma 16, 161 (1969)], with minor modifications in [Mattern, J.: Studies on the Drug Sensitivity of Short Term Cultured Tumor Cell Sus-10 pensions. Human Tumors in Short Term Culture (Dendy, P.P. Ed.) P. 301, Academic Press 1976]. The Cox-based comparative risk model was used to study survival and determine optimal dosing by W.H. Carter et al. according to [Cancer Res. 42, 2963 (1982)].

15

The therapeutic effect of the object of the invention means that it is possible to prevent the characteristic symptoms of the disease in biological targets that have tumors that tend to grow, inhibit the shortening of the life expectancy of the biological target and increase or increase the number of tumor cells. Tumor growth can be observed clinically or experimentally in vivo, i.e., in experimental animals, or in vitro, for example, in tissue cultures made of tumors. Tumor growth can be assessed by measuring tumor weight, or more effectively by measuring radioactivity after the addition of certain substances of natural origin such as amino acids (e.g. valine, leucine, natural amino acid mixture), nucleic bases (e.g. adenine) to the tumor. , nucleosides (thymidine, uridine), their analogs 30 and (5-iododeoxyuridine), etc., which are labeled with radioactive atoms such as 14C, 3H, etc. The useful curative effect of the compounds of formula I has been demonstrated in experiments on abdominal sarcoma 37 (S37). , HK and / or Ehrlich solid tumors using these compounds orally and parenterally Compared to untreated control animals, the average weight of tumors in the treated animals (examples) was found to be significantly lower. The compounds of formula 107256 6 I are further useful in increasing the life span of a suitable biological target such as mice and rats with S37, HK, STE, LsG and Y and / or leukemias P388 and L1210, especially after oral administration. The lethal nature of the test system used to exemplify the antitumor activity of the compounds is illustrated by comparing the eLoon residence time of concurrently treated animals (which lived longer) and untreated control animals. In the typical experiments of the examples, 10 experimental groups included ten animals and the treated animal groups survived longer than the untreated controls.

6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline hydrochloride, a typical compound of the chemical group of formula I after intravenous administration of tea, a significant increase in DBA2 survival in mice with leukemia P388 was observed. The compounds and their salts show immediate cytotoxicity against tumor cells of Yoshida, Ehrlich and Gardner tumors and L1210 leukemia and its durable variant after mitoxan-20 throne treatment. The compounds of the formula I can also be used as inhibitors of DNA, RNA and protein biosynthesis of tumor cells. This could be clearly deduced from the examples. Inhibition of any of the aforementioned important biosynthesis can be achieved as a result of anti-tumor activity of the cytotoxic agents. The compounds described herein may be administered to suitable biological targets, in particular mammals, because of their therapeutic, antitumor effects, not only by administration of conventional dosage forms, but also as an active ingredient in a conventional, suitable, non-toxic pharmaceutical carrier, dissolved or suspended in, e.g. polyethylene or polypropylene alcohols, etc. The drug is preferably administered orally. The dose will depend on the type of tumor for which treatment is sought, the type of biological subject, weight, body surface area, location of the tumor, its morphological type, frequency of treatment, etc .; the bioavailable oral dose is 400 mg / kg (1200 mg / m2).

ED 95 was 225 mg / kg p.o. (675 mg / m 2) of a typical compound in a mouse with L1210 leukemia DBA2. Intravenous doses represented approximately half of the oral dose of the drug, and repeated oral administration lasted five days. The compounds are not very toxic, the LD 50 in mice is about 700 mg / kg p.o.

It will be appreciated that therapeutically useful effects can be expected when dosed in amounts that are completely non-toxic to the mammalian organism in question. Bioassays suggest that a single oral dose of 675 mg / m2 is tolerable and effective in humans.

20

Figure 1 shows the dosing response curves for a typical compound of Formula I with X-2 (see Example 8) when tested on Yoshida's water abdominal tumor bearing rats.

25

The process for the preparation of the compounds of the formula I as well as their biological studies are described in the following non-limiting examples. Melting points were determined in the Kofler block and have not been corrected, yields being 30 stoichiometric percent of theoretical value.

Example 1 6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline (I; X = 2)

A suspension of 5 g of 11-oxo-11 H -indeno [1,2-c] isocoumarin (II, m.p. 258 ° C) in 60 ml of dimethylform; amide was treated by the addition of 3 g of N- (2-hydroxy- (1072566) -ethyl) ethylenediamine in one portion and the mixture was stirred while heating to 110 ° C. After heating for about one hour, the bright red solution is cooled to laboratory temperature and the precipitated product is filtered off with suction after washing for 12 hours, washed with 60 ml of ethanol and dried at 60 ° C to give 6.0 g (89%) ) product which melts at 184 ° C. Purification of the title indenoisoquinoline (I; X = 2) is accomplished by crystallization from a mixture containing dimethylformamide and ethanol. The compound forms small orange needles that melt at 184 ° C.

Example 2 6- [3- (2-Hydroxyethyl) aminopropyl] -5,11-dioxo-5,6-15 dihydro-11 H -indeno [1,2-c] isoquinoline (I; X = 3)

Under the same conditions (see Example 1), 5.9 g of 1-methoxy-2- (2-methoxycarbonylphenyl) -1-inden-3-one (III, m.p. 116-118 ° C) are condensed at 110 ° C. 2- (3-aminopropylamino) ethanol in 60 mL of dimethylformamide.

20

When the reaction is complete, 70 ml of distilled water are added gradually. The mixture was cooled to 3-5 ° C, the precipitated red-orange crystalline material was separated after 20 hours of suction, washed with water (100 ml), and after drying at 60 ° C (mp 151-153 ° C, yield 5). 35 g, 80%) was crystallized from ethanol. The product has a melting point of 155 ° C.

Example 3 6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-1 H -indeno [1,2-c] isoquinoline (I; X = 2)

A mixture of 1 g of 6- (2-chloroethyl) 5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isocoline (IV, X = 2, mp 214-215 ° C). , 1 g of dry aminoethanol and 1 g of anhydrous 35 potassium carbonate in 30 ml of dimethylformamide were heated by heating at 100-110 ° C and held at this temperature for two hours. The hot mixture was filtered and the filtered product was washed with 10 mL of ethanol. After two to 10 7256 hours, the crystalline material separated in a refrigerator (5 ° C) was filtered off with suction, washed with ethanol and dried at 60 ° C. Yield 0.7 g (65% of theory) m.p. 184 ° C. The material can be purified as described in Example 1.

Example 4 6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline hydrochloride (I; X = 2) 10 120 ml To distilled water heated to 75-80 ° C was added 6 g of the substance I (X = 2) base and, after brief stirring, treated with 30 ml of concentrated hydrochloric acid. After stirring for 5 minutes, 300 ml of ethanol heated to 50-15 ° C was added. The suspension was refluxed for 10 minutes and after reconstitution was carefully filtered and left to crystallize at 20 ° C for 20 hours. The yield was 6.1 g (91% of theory).

Example 5 Tumor of 6- [2- (2-hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline (substance I, X = 2) in mice following oral administration.

Eighty female H mice, weighing an average of 20 g, were divided into four groups: one control group and three experimental groups, each containing 20 animals. A lethal dose of Sa37 sarcoma vesicant fluid was intraperitoneally implanted in all 30 animals. The animals in the test groups were treated with a compound suspended in water. The concentration of the substance in the suspension was such that a 0.6, 0.4 and / or 0.2 ml portion of the suspension was p.o. corresponded to doses of 240, 160 and / or 180 mg / kg p.o. The drug was administered to the test animals once daily after transfusion of the cas-35 litter. On the tenth day of tumor transplantation, half of the animals in each group were sacrificed by pre-anesthesia, the abdomen was evacuated after abdominal opening, and tumor weight was determined for each animal 1072 (56 at 10 before and after abdominal opening and abdomen removal). Statistically significantly lower mean tumor weights, as well as smaller mean tumor cell fractions in aqueous gastric fluid, were observed in treated animals compared to untreated treated animals had significantly longer survival times (Student's t-test, p <0.001) compared to untreated control animals. The results of the experiment are shown in the following table: 6- [2- (2-hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-cisoquinoline (substance I). , X = 2) antitumor effect in S37 sarcoma bearing chimeric 20

Substance Dose Tumor Survival Size (mg / kg) Weight Time Abdomen _EL-Oj · _CT / C,%) _ (T / C,%) _ (T / C,%) 25 I 240 42e) 119b> 47c) ( X = 2) 160 59c) 111 65c) 30 80 61c) 107 64c) b) p = 0.01 c) p = 0.001 Example 6 6- [2- (2-hydroxyethyl) aminoethyl] -5,11-dioxo -5,6-dimethyl. hydro-11 H -indeno [1,2-c] isoquinoline (substance I, X = 2) and 6- 107 256 11 [3- (2-hydroxyethyl) aminopropyl] -5,11-dioxo-5,6-dihydro - Antitumor activity of 11 H -indeno [1,2-c] isoquinoline (substance I, X-3) in mice following oral administration.

5

In a similar experiment in which animals were transplanted with SA37 sarcoma, substance I (X = 2) was administered for seven daily doses and substance I (X = 3) for four days. The results of the experiment are shown in the following table: 6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline (substance I, X = 2) and 6- 13- (2-hydroxyethyl) aminopropyl] -5,11-dioxo-5,6-dihydro-11 H -indeno [1,2-c] isoquinoline (substance I, X = 3). antitumor effect in S37-bearing mice

Substance Dose Tumor Survival Size (mg / kg) - Weight Time Abdomen _p.o. fT / C. %) (T / C,%) _ (T / C.%) 20 I 30 32b) 86 47b) (X = 2) 20 64b) 129 73Ä) 25 10 66b> 129 73b> I 30 35b) poison. 43b) (X = 3) 20 56c) 99 62c) 30 10 70b) 119 80a) a) p <0.05 b) p <0.01 35 c) p <0.001 myrk. = toxic dose * »12 107256

Example 7 Tumor of 6- [2- (2-hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dih γ-dro-11 H -indeno [1,2-c] isoquinoline (substance I, X = 2) activity in mice after oral administration of the drug.

Sixty female H mice, weighing an average of 20 g, were divided into three groups: one control group and two experimental groups, each containing 20 animals. A lethal dose of 40 Ehrlich tumor homo-10 genes was subcutaneously transferred to all animals.

The animals in the test groups were treated with compounds suspended in water. The concentration of the substance in the suspension was such that a 0.4 and / or 0.2 ml portion of the suspension was p.o. corresponded to a dose of 400 and / or 200 mg / kg p.o. The drug was administered to 15 experimental animals once, on the fifth day after tumor transplantation. On the fourteenth day of tumor transplantation, half of the animals in each group were sacrificed by ether anesthesia, and the tumor was removed and weighed. Survival times of the remaining animals were quoted and survival times were monitored. Statistically significantly lower mean tumor weights were observed in the treated animals compared to the untreated control group (Student's t test, p <0.01). It was also observed that treated animals survived longer than untreated control animals. The mean survival times of the treated animals were significantly longer '(Student's t test, p <0.05) compared to the untreated animals. The results of the experiment are shown in the following table:

Substance Dose Tumor Survival (mg / kg) Weight Time _P.o. (T / C,%) _ (T / C.% 1_ I 400 31b) 152b) 35 (X = 2) 200 79 "> 111 a) p = 0.05. b) p = 0.01 •: i 13 107256

Example 8 6- [2- (2-Hydroxyethyl) aminoethyl] -5,11-dioxo-5,6-dihydro-1H-indeno [1,2-c] isoquinoline (substance I, X = 2) effect in rats following oral and parenteral 5-drug administration.

Seventy newborn female Wistar rats weighing 63.0-64.8 g were divided into seven groups: one control group and six experimental groups, each containing 10 animals. A lethal dose of Yoshida 10 aqueous retinal fluid from reticuloendothelial cancer was intraperitoneally transferred to all animals. Animals in the test groups were treated with the compound suspended in water. The concentration of the substance in the suspension was such that a dose of 0.6, 0.4 and / or 0.2 ml of the suspension corresponded to 200, 100 and / or 15 mg of 50 mg / kg p.o. or 40, 20 and / or 10 mg / kg s.c.

The drug was administered to the test animals once daily for five consecutive days, starting on the first day after tumor transplantation. The survival time of all animals was monitored. Treated animals were observed to live longer than untreated control animals. The mean survival times of the treated animals were significantly longer (Student's t test, p <0.01) compared to the untreated animals. The results of the experiment are shown in the following table and illustrated in Figure 1.

Substance Drug Dose Survival Administration Form (mg / kg) Time f) _ (% of control 30 I p.o. 200 219b, d) (X = 2) 100 230b, e) 50,132 ** s.c. 40 86 20 1391 35 10 2032 »p-0.05, b) p = 0.01, d) 3 LTS (long term survival), e) 1 LTS, f) T / C,% 107256 14

Example 9 Antitumor activity of 6 - [(2-hydroxyethyl) amino] -5,11-dioxo-5,6-dihydro-11H-indeno [1,2-c] isoquinoline (substance I, Χ = 0) in mice.

5 In an experiment performed on animals that had been moved

Sa37 sarcoma, substance I (X = 0) was administered eight times daily (as in Example 6). Statistically significantly lower mean tumor weights, such as lower mean tumor cell fractions in the aqueous-10 medium, were observed in the treated animals compared to the untreated control group (Student's t test p <0.001) at doses of 50 mg / kg p.o. (60 and 68%) and / or 20 mg / kg s.c. (68 and 71%).

Example 10 Antitumor effect of 6 - [(2-hydroxyethyl) amino] -5,11-dioxo-5,6-dihydro-11H-indenofl, 2-c] isoquinoline (substance I, X = O) in oral mice after administration.

In the context of an Ehrlich's tumor assay (solid form, see Example 7), administration of the drug to experimental animals in a single dose of 100 mg / kg p.o. significantly reduced mean tumor weight (72% in treated animals compared to untreated control group). When administered eight times, starting on the first day of tumor transplantation, the mean tumor weight decreased significantly (p <0.05) at doses of 50 mg / kg p.o. x 8. The median survival time was longer (115%, p <0.05) compared to the untreated ver-30 rock group at 25 mg / kg p.o. eight times a day. j

Example 11

Cell toxicity of salt of Substance I (X = 2) as compared to clinically useful drugs.

The effect of the addition of [3 H] thymidine and [14 C] uridine on the Yoshida aqueous gastric cell fraction, insoluble in trichloroacetic acid, serves as a measure of cellular toxicity.

107256 The IC50 value corresponds to the concentration of the cytotoxic agent, which reduces the 3H and 14C additions to 50% of unaffected control cells. The test results are shown in the following table.

5

Effect of Substance I (X = 2) Hydrochloride on Yoshida Aquatic Tumor Cells.

10

Substance Molecular weight Precursor IC 50 - (nmol.

Hydrochloride 15 [Uracil-U-14C] uridine 7 DOXORUBICIN 548.0 [6-3H] Thymidine 16 [Uracil-U-14C] uridine 8 20 MITOXANTRON 517.4 [6-3H] Thymidine 25 [Uracil-U-14C] uridine 23 25

Example 12

In vitro cellular toxicity of Substance I (X = 2) against L1210 leukemia cells and its mitoxantrone resistant variant L1210 / MX.

30

As previously described, the effect of the addition of the [14C] amino acid mixture on L1210 leukemia cells and / or L1210 / MX cells, the fraction insoluble in trichloroacetic acid, was monitored as a measure of cross resistance between substance I (X = 2) and mitoxantrone. The test results are shown in the following table.

16 10721) 6

Substance Tumor Precursor IC 50 ___ (umol. I'1)

I (X-2) L1210 [U-14C] Amino Acid Mixture 7J

Base 5 L (X = 2) L1210 / MX [U-14C] Amino Acid Mixture 1L9

Base

The results show that the cross resistance is only partial. The agents of this application may be clinically useful in cases where the tumor is resistant to mitoxantrone.

Claims (6)

17 107256 A process for the preparation of an antitumor 6- (2-hydroxyethylamino or 2-hydroxyethylaminoalkyl) -5,11-dioxo-5,6-5-dihydro-11H-indeno [1,2-c] isoquinoline derivative of the general formula for the preparation of a salt of N / (Ch 2) 0 (I) 10 or a salt thereof with an inorganic or organic acid wherein X represents a number of carbon atoms from 0 to 5 in the aminoalkyl group bound to the nitrogen atom at position 6 of the indenoisoquinoline base a) reacting 15 a) 11-oxo-1H-indeno [1,2-c] isocoumarin of the formula (II) 20 (18) 10721) 6 with N- (hydroxyethyl) diamine or with N- (hydroxyethyl) alkylenediamine containing 1 to 5 carbon atoms in its alkyl chain in a suitable aprotic solvent, preferably dimethylformamide, and at elevated temperature, or b) 1-methoxy-2- (methoxycarbonylphenyl) -1-inden-3 -L is of the formula COOCH3 (m) is reacted with N- (hydroxyethyl) diamine or N- (hydroxyethyl) alkylenediamine containing 1 to 5 carbon atoms in its alkyl chain at an elevated temperature in a suitable solvent, preferably dimethylformamide, or c) a compound of formula I wherein X is 2-5,6- (chloroalkyl) -5,11-dioxo-5,6-dihyc-20ro-1 H -indeno [1,2-c] isoquinoline of the formula: * * '(CH 2) x -C 10 (IV) 107256 19 wherein X corresponds to a number of carbon atoms in the 2-5 alkyl chain is reacted with 2-aminoethanol at an elevated temperature and in a suitable solvent, preferably dimethylformamide, and in the presence of anhydrous potassium carbonate. . Process according to claim 1, characterized in that a compound of the formula I is prepared wherein n = 2.10 Process according to claim 1, characterized in that a compound of the formula I is prepared wherein n = 3. 15 Patent Claims